Cytokine inhibitors

ABSTRACT

Disclosed are compounds of formula (I) 
                         
which inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

APPLICATION DATA

This application claims benefit to U.S. provisional application Ser. No.60/604,254 filed Aug. 25, 2004.

BACKGROUND OF THE INVENTION

1. Technical Field

This invention relates to compounds of formula (I)

The compounds of the invention inhibit production of cytokines involvedin inflammatory processes and are thus useful for treating diseases andpathological conditions involving inflammation such as chronicinflammatory disease. This invention also relates to processes forpreparing these compounds and to pharmaceutical compositions comprisingthese compounds.

2. Background Information

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are importantbiological entities collectively referred to as proinflammatorycytokines which play a role in cytokine mediated diseases. These, alongwith several other related molecules, mediate the inflammatory responseassociated with the immunological recognition of infectious agents. Theinflammatory response plays an important role in limiting andcontrolling pathogenic infections.

Elevated levels of proinflammatory cytokines are also associated with anumber of diseases of autoimmunity such as toxic shock syndrome,rheumatoid arthritis, osteoarthritis, diabetes and inflammatory boweldisease (Dinarello, C. A., et al., 1984, Rev. Infect. Disease 6:51). Inthese diseases, chronic elevation of inflammation exacerbates or causesmuch of the pathophysiology observed. For example, rheumatoid synovialtissue becomes invaded with inflammatory cells that result indestruction to cartilage and bone (Koch, A. E., et al., 1995, J. Invest.Med. 43: 28-38). Studies suggest that inflammatory changes mediated bycytokines may be involved in endothelial cell pathogenesis includingrestenosis after percutaneous transluminal coronary angioplasty (PTCA)(Tashiro, H., et al., 2001 Mar, Coron Artery Dis 12(2):107-13). Animportant and accepted therapeutic approach for potential drugintervention in these diseases is the reduction of proinflammatorycytokines such as TNF (also referred to in its secreted cell-free formas TNFα) and IL-1β. A number of anti-cytokine therapies are currently inclinical trials. Efficacy has been demonstrated with a monoclonalantibody directed against TNFα in a number of autoimmune diseases(Heath, P., “CDP571: An Engineered Human IgG4 Anti-TNFα Antibody” IBCMeeting on Cytokine Antagonists, Philadelphia, Pa., Apr. 24-5, 1997).These include the treatment of rheumatoid arthritis, Crohn's disease andulcerative colitis (Rankin, E. C. C., et al., 1997, British J Rheum. 35:334-342 and Stack, W. A., et al., 1997, Lancet 349: 521-524). Themonoclonal antibody is thought to function by binding to both solubleTNFα and to membrane bound TNF.

A soluble TNFα receptor has been engineered that interacts with TNFα.The approach is similar to that described above for the monoclonalantibodies directed against TNFα; both agents bind to soluble TNFα, thusreducing its concentration. One version of this construct, called Enbrel(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase IIIclinical trial for the treatment of rheumatoid arthritis (Brower et al.,1997, Nature Biotechnology 15: 1240). Another version of the TNFαreceptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) hasdemonstrated efficacy in various animal models of allergic lunginflammation and acute lung injury. Ro 45-2081 is a recombinant chimericmolecule constructed from the soluble 55 kDa human TNF receptor fused tothe hinge region of the heavy chain IgG1 gene and expressed ineukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143).

IL-1 has been implicated as an immunological effector molecule in alarge number of disease processes. IL-1 receptor antagonist (IL-1ra) hadbeen examined in human clinical trials. Efficacy has been demonstratedfor the treatment of rheumatoid arthritis (Antril, Amgen). In a phaseIII human clinical trial IL-1ra reduced the mortality rate in patientswith septic shock syndrome (Dinarello, 1995, Nutrution 11, 492).Osteoarthritis is a slow progressive disease characterized bydestruction of the articular cartilage. IL-1 is detected in synovialfluid and in the cartilage matrix of osteoarthritic joints. Antagonistsof IL-1 have been shown to diminish the degradation of cartilage matrixcomponents in a variety of experimental models of arthritis (Chevalier,1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator ofcardiovascular homeostasis, neurotransmission and immune function;recently it has been shown to have important effects in the modulationof bone remodeling. Cytokines such as IL-1 and TNF are potentstimulators of NO production. NO is an important regulatory molecule inbone with effects on cells of the osteoblast and osteoclast lineage(Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion ofbeta-cell destruction leading to insulin dependent diabetes mellitusshows dependence on IL-1. Some of this damage may be mediated throughother effectors such as prostaglandins and thromboxanes. IL-1 can effectthis process by controlling the level of both cyclooxygenase II andinducible nitric oxide synthetase expression (McDaniel et al., 1996,Proc Soc Exp Biol Med. 211, 24).

Inhibitors of cytokine production are expected to block induciblecyclooxygenase (COX-2) expression. COX-2 expression has been shown to beincreased by cytokines and it is believed to be the isoform ofcyclooxygenase responsible for inflammation (M. K. O'Banion et al.,Proc. Natl. Acad. Sci. U.S.A, 1992, 89, 4888.) Accordingly, inhibitorsof cytokines such as IL-1 would be expected to exhibit efficacy againstthose disorders currently treated with COX inhibitors such as thefamiliar NSAIDs. These disorders include acute and chronic pain as wellas symptoms of inflammation and cardiovascular disease.

Elevation of several cytokines has been demonstrated during activeinflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1and IL-1ra is present in patients with IBD. Insufficient production ofendogenous IL-1ra may contribute to the pathogenesis of IBD (Cominelli,et al., 1996, Aliment Pharmacol Ther. 10, 49). Alzheimer disease ischaracterized by the presence of beta-amyloid protein deposits,neurofibrillary tangles and cholinergic dysfunction throughout thehippocampal region. The structural and metabolic damage found inAlzheimer disease is possibly due to a sustained elevation of IL-1(Holden, et al., 1995, Med Hypotheses, 45, 559). A role for IL-1 in thepathogenesis of human immunodeficiency virus (HIV) has been identified.IL-1ra showed a clear relationship to acute inflammatory events as wellas to the different disease stages in the pathophysiology of HIVinfection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54). IL-1 andTNF are both involved in periodontal disease. The destructive processassociated with periodontal disease may be due to a disregulation ofboth IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).

Proinflammatory cytokines such as TNFα and IL-1β are also importantmediators of septic shock and associated cardiopulmonary dysfunction,acute respiratory distress syndrome (ARDS) and multiple organ failure.In a study of patients presenting at a hospital with sepsis, acorrelation was found between TNFα and IL-6 levels and septiccomplications (Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNFαhas also been implicated in cachexia and muscle degradation, associatedwith HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289).Obesity is associated with an increase incidence of infection, diabetesand cardiovascular disease. Abnormalities in TNFα expression have beennoted for each of the above conditions (Loffreda, et al., 1998, FASEB J.12, 57). It has been proposed that elevated levels of TNFα are involvedin other eating related disorders such as anorexia and bulimia nervosa.Pathophysiological parallels are drawn between anorexia nervosa andcancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). Aninhibitor of TNFα production, HU-211, was shown to improve the outcomeof closed brain injury in an experimental model (Shohami, et al., 1997,J Neuroimmunol. 72, 169). Atherosclerosis is known to have aninflammatory component and cytokines such as IL-1 and TNF have beensuggested to promote the disease. In an animal model an IL-1 receptorantagonist was shown to inhibit fatty streak formation (Elhage et al.,1998, Circulation, 97, 242).

TNFα levels are elevated in airways of patients with chronic obstructivepulmonary disease and it may contribute to the pathogenesis of thisdisease (M. A. Higham et al., 2000, Eur. Respiratory J, 15, 281).Circulating TNFα may also contribute to weight loss associated with thisdisease (N. Takabatake et al., 2000, Amer. J. Resp. & Crit. Care Med.,161 (4 Pt 1), 1179). Elevated TNFα levels have also been found to beassociated with congestive heart failure and the level has beencorrelated with severity of the disease (A. M. Feldman et al., 2000, J.Amer. College of Cardiology, 35, 537). In addition, TNFα has beenimplicated in reperfusion injury in lung (Borjesson et al., 2000, Amer.J. Physiol., 278, L3-12), kidney (Lemay et al., 2000, Transplantation,69, 959), and the nervous system (Mitsui et al., 1999, Brain Res., 844,192).

TNFα is also a potent osteoclastogenic agent and is involved in boneresorption and diseases involving bone resorption (Abu-Amer et al.,2000, J. Biol. Chem., 275, 27307). It has also been found highlyexpressed in chondrocytes of patients with traumatic arthritis(Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNFα hasalso been shown to play a key role in the development ofglomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78,1625).

The abnormal expression of inducible nitric oxide synthetase (iNOS) hasbeen associated with hypertension in the spontaneously hypertensive rat(Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in theexpression of iNOS and therefore may also have a role in thepathogenesis of hypertension (Singh et al., 1996, Amer. J Hypertension,9, 867).

IL-1 has also been shown to induce uveitis in rats which could beinhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol.and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have beenshown to stimulate proliferation of acute myelogenous leukemia blasts(Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essentialfor the development of both irritant and allergic contact dermatitis.Epicutaneous sensitization can be prevented by the administration of ananti- IL-1 monoclonal antibody before epicutaneous application of anallergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Dataobtained from IL-1 knock out mice indicates the critical involvement infever for this cytokine (Kluger et al., 1998, Clin Exp PharmacolPhysiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 andIL-8 initiate the acute-phase reaction which is stereotyped in fever,malaise, myalgia, headaches, cellular hypermetabolism and multipleendocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).The production of these inflammatory cytokines rapidly follows trauma orpathogenic organism invasion.

Other proinflammatory cytokines have been correlated with a variety ofdisease states. IL-8 correlates with influx of neutrophils into sites ofinflammation or injury. Blocking antibodies against IL-8 havedemonstrated a role for IL-8 in the neutrophil associated tissue injuryin acute inflammation (Harada et al., 1996, Molecular Medicine Today 2,482). Therefore, an inhibitor of IL-8 production may be useful in thetreatment of diseases mediated predominantly by neutrophils such asstroke and myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, hemodialysis, leukopherisis,granulocyte transfusion associated syndromes, and necrotizingenterocolitis.

Rhinovirus triggers the production of various proinflammatory cytokines,predominantly IL-8, which results in symptomatic illnesses such as acuterhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).

Other diseases that are effected by IL-8 include myocardial ischemia andreperfusion, inflammatory bowel disease and many others.

The proinflammatory cytokine IL-6 has been implicated with the acutephase response. IL-6 is a growth factor in a number in oncologicaldiseases including multiple myeloma and related plasma cell dyscrasias(Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has alsobeen shown to be an important mediator of inflammation within thecentral nervous system. Elevated levels of IL-6 are found in severalneurological disorders including AIDS dementia complex, Alzheimer'sdisease, multiple sclerosis, systemic lupus erythematosus, CNS traumaand viral and bacterial meningitis (Gruol, et al., 1997, MolecularNeurobiology 15: 307). IL-6 also plays a significant role inosteoporosis. In murine models it has been shown to effect boneresorption and to induce osteoclast activity (Ershler et al., 1997,Development and Comparative Immunol. 21: 487). Marked cytokinedifferences, such as IL-6 levels, exist in vivo between osteoclasts ofnormal bone and bone from patients with Paget's disease (Mills, et al.,1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shownto be involved in cancer cachexia. The severity of key parameters ofcachexia can be reduced by treatment with anti IL-6 antibodies or withIL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther.1, 107). Several infectious diseases, such as influenza, indicate IL-6and IFN alpha as key factors in both symptom formation and in hostdefense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpressionof IL-6 has been implicated in the pathology of a number of diseasesincluding multiple myeloma, rheumatoid arthritis, Castleman's disease,psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997,Protein Sci. 6, 929). Compounds that interfered with the production ofcytokines including IL-6, and TNF were effective in blocking a passivecutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41,1050).

GM-CSF is another proinflammatory cytokine with relevance to a number oftherapeutic diseases. It influences not only proliferation anddifferentiation of stem cells but also regulates several other cellsinvolved in acute and chronic inflammation. Treatment with GM-CSF hasbeen attempted in a number of disease states including burn-woundhealing, skin-graft resolution as well as cytostatic and radiotherapyinduced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF alsoappears to play a role in the replication of human immunodeficiencyvirus (HIV) in cells of macrophage lineage with relevance to AIDStherapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41).Bronchial asthma is characterised by an inflammatory process in lungs.Involved cytokines include GM-CSF amongst others (Lee, 1998, J R CollPhysicians Lond 32, 56).

Interferon γ (IFN γ) has been implicated in a number of diseases. It hasbeen associated with increased collagen deposition that is a centralhistopathological feature of graft-versus-host disease (Parkman; 1998,Curr Opin Hematol. 5, 22). Following kidney transplantation, a patientwas diagnosed with acute myelogenous leukemia. Retrospective analysis ofperipheral blood cytokines revealed elevated levels of GM-CSF and IFN γ.These elevated levels coincided with a rise in peripheral blood whitecell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). Thedevelopment of insulin-dependent diabetes (Type 1) can be correlatedwith the accumulation in pancreatic islet cells of T-cells producing IFNγ (Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN γ along with TNF,IL-2 and IL-6 lead to the activation of most peripheral T-cells prior tothe development of lesions in the central nervous system for diseasessuch as multiple sclerosis (MS) and AIDS dementia complex (Martino etal., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result inarterial disease that can lead to cardiac and cerebral infarction. Manyactivated immune cells are present in these lesions, mainly T-cells andmacrophages. These cells produce large amounts of proinflammatorycytokines such as TNF, IL-1 and IFN γ. These cytokines are thought to beinvolved in promoting apoptosis or programmed cell death of thesurrounding vascular smooth muscle cells resulting in theatherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76).Allergic subjects produce mRNA specific for IFN γ following challengewith Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342).The expression of a number of cytokines, including IFN γ has been shownto increase following a delayed type hypersensitivity reaction thusindicating a role for IFN γ in atopic dermatitis (Szepietowski, et al.,1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologicstudies were performed in cases of fatal cerebral malaria. Evidence forelevated IFN γ amongst other cytokines was observed indicating a role inthis disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501).The importance of free radical species in the pathogenesis of variousinfectious diseases has been established. The nitric oxide synthesispathway is activated in response to infection with certain viruses viathe induction of proinflammatory cytokines such as IFN γ (Akaike, etal., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronicallyinfected with hepatitis B virus (HBV) can develop cirrhosis andhepatocellular carcinoma. Viral gene expression and replication in HBVtransgenic mice can be suppressed by a post-transcriptional mechanismmediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer SeminImmunopathol. 17, 261). IFN γ can selectively inhibit cytokine inducedbone resorption. It appears to do this via the intermediacy of nitricoxide (NO) which is an important regulatory molecule in bone remodeling.NO may be involved as a mediator of bone disease for such diseases as:rheumatoid arthritis, tumor associated osteolysis and postmenopausalosteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studieswith gene deficient mice have demonstrated that the IL-12 dependentproduction of IFN y is critical in the control of early parasiticgrowth. Although this process is independent of nitric oxide the controlof chronic infection does appear to be NO dependent (Alexander et al.,1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an importantvasodilator and convincing evidence exists for its role incardiovascular shock (Kilboum, et al., 1997, Dis Mon. 43, 277). IFN γ isrequired for progression of chronic intestinal inflammation in suchdiseases as Crohn's disease and inflammatory bowel disease (IBD)presumably through the intermediacy of CD4+ lymphocytes probably of theTH 1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). Anelevated level of serum IgE is associated with various atopic diseasessuch as bronchial asthma and atopic dermatitis. The level of IFN γ wasnegatively correlated with serum IgE suggesting a role for IFN γ inatopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).

WO 01/01986 discloses particular compounds alleged to having the abilityto inhibit TNF-alpha. Certain compounds disclosed in WO 01/01986 areindicated to be effective in treating the following diseases: dementiaassociated with HIV infection, glaucoma, optic-neuropathy, opticneuritis, retinal ischemia, laser induced optic damage, surgery ortrauma-induced proliferative vitreoretinopathy, cerebral ischemia,hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbonmonoxide or manganese or cyanide poisoning, Huntington's disease,Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosisand other demyelinating diseases, amyotrophic lateral sclerosis, headand spinal cord trauma, seizures, convulsions, olivopontocerebellaratrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-relatedneuropathy, MERRF and MELAS syndromes, Leber's disease, Wernicke'sencephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia,hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyricaminoaciduria, sulfite oxidase deficiency, combined systems disease,lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drugaddiction, drug tolerance, drug dependency, depression, anxiety andschizophrenia. WO 02/32862 discloses that inhibitors of pro-inflammatorycytokines including TNFα are allegedly useful for treating acute andchronic inflammation in the lung caused by inhalation of smoke such ascigarette smoke. TNFα anatagonists are apparently also useful for thetreatment of endometriosis, see EP 1022027 A1. Infliximab, in clinicaltrials for RA, has also been indicated to be useful for treating variousinflammatory diseases including Behcet's disease, uveitis and ankylosingspondylitis. Pancreatitis may also be regulated by inflammatory mediatorproduction, see J Surg Res 2000 May 15 90(2)95-101; Shock 1998 Sep.10(3):160-75. p38MAP kinase pathway plays an role in B.burgdorferi-elicited infammation and may be useful in treatinginflammation induced by the Lyme disease agent. Anguita, J. et. al., TheJournal of Immunology, 2002,168:6352-6357.

Compounds which modulate release of one or more of the aforementionedinflammatory cytokines can be useful in treating diseases associatedwith release of these cytokines. For example, WO 98/52558 disclosesheteroaryl urea compounds which are indicated to be useful in treatingcytokine mediated diseases. WO 99/23091 discloses another class of ureacompounds which are useful as anti-inflammatory agents. WO 99/32463relates to aryl ureas amd their use in treating cytokine diseases andproteolytic enzyme mediated disease. WO 00/41698 discloses aryl ureassaid to be useful in treating p38 MAP kinase diseases.

Compounds active against p38 MAP kinase can also be useful for treatingvarious types of cancers as described in WO 03/068223.

U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclicsubstituted urea compounds which are described as being useful fortreating hypercholesterolemia and atheroclerosis. Di-substituted aryland heteroaryl compounds are also disclosed in U.S. Pat. Nos. 6,080,763;6,319,921; 6,297,381 and 6,358,945. The compounds in the patents arealleged to possess anti-cytokine activity and are therefore useful intreating diseases associated with inflammation.

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of cytokine mediateddiseases. Therefore a need exists for small molecule inhibitors fortreating these diseases with optimized efficacy, pharmacokinetic andsafety profiles.

BRIEF SUMMARY OF THE INVENTION

The work cited above supports the principle that inhibition of cytokineproduction with small molecule compounds will be beneficial in thetreatment of various disease states.

It is therefore an object of the invention to provide compounds offormula (I)

It is a further object of the invention to provide methods for treatingcytokine mediated diseases and pathological conditions involvinginflammation such as chronic inflammatory disease, using the novelcompounds of the invention.

It is yet a further object of the invention to provide pharmaceuticalcompositions and processes of preparation of the above-mentioned novelcompounds.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In a broad generic aspect of the invention there is provided a compoundof the formula (I)

wherein:

-   n is 1, 2 or 3;-   Ar is chosen from rings (i), (ii) (iii) and (iv) below:

wherein one of A or B is nitrogen and the other is carbon, R¹ iscovalently attached to either A or B, and when nitrogen is N—R¹ thedouble bond between A and B is not present;

-   R¹ is chosen from hydrogen, NO₂, —N(R^(c))₂, J-C(O)—N(R^(c))—,    J-S(O)_(m)—N(R^(c))—, or R¹ is chosen from C₁₋₆ alkyl, C₃₋₇    cylcoalkyl, C₁₋₅ alkoxyl or C₃₋₇ cycloalkoxyl, C₁₋₅ alkylthiol or    C₃₋₇ cycloalkylthiol, C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy,    C₁₋₅ acylamino, C₂₋₅ alkenyl, C₂₋₅ alkynyl, heterocycle, heteroaryl    and nitrile, each of the aforementioned where possible are    optionally partially or fully halogenated or are optionally further    substituted with alkylsulfonylamino, alkoxyl, amino, alkylamino,    dialkylamino, hydroxyl, oxo, nitro or nitrile;    -   or R¹ is, where P can be 0, >CR⁹ or >NR⁹

-   -   wherein g is 1 to 4, preferably 1 to 2,    -   R⁹ is chosen from C₁₋₆ alkyl, C₃₋₇ cylcoalkyl, C₁₋₅ alkoxyl or        C₃₋₇ cycloalkoxyl, C₁₋₅ alkylthiol or C₃₋₇ cycloalkylthiol, C₁₋₅        acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, C₂₋₅        alkenyl, C₂₋₅ alkynyl, heterocycle, heteroaryl and nitrile, each        of the aforementioned where possible are optionally partially or        fully halogenated or are optionally further substituted with        alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,        hydroxyl, oxo, nitro or nitrile;    -   R² is chosen from hydrogen, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy,        C₁₋₅ alkylC₁₋₅ alkoxy, hydroxy, hydroxy C₁₋₅ alkyl, oxo, C₁₋₅        alkylS(O)_(m)— and amino optionally mono- or di-substituted by        C₁₋₅ alkyl, aryl or aryl C₁₋₅ alkyl;

wherein

-   R^(1′), is chosen from hydrogen, J-S(O)_(m)—, J-S(O)_(m)—NH—,    J-NHS(O)_(m)—, C₁₋₆ alkyl, C₃₋₇ cylcoalkyl, C₁₋₅ alkoxyl or C₃₋₇    cycloalkoxyl, C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₂₋₅    alkenyl, C₂₋₅ alkynyl, heterocycle, heterocycle C₁₋₆ alkyl,    heteroaryl, heteroarylC₁₋₆ alkyl and nitrile, each of the    aforementioned where possible are optionally partially or fully    halogenated or are optionally further substituted with    alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,    hydroxyl, oxo, nitro or nitrile;-   R^(2 ′)is chosen from nitrile, J-S(O)_(m)—, J-O—C(O)—O—,    NH₂—C(O)—(CH₂)_(n)—, H, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, C₁₋₅ alkyl    C₁₋₅ alkoxy, hydroxy, hydroxy C₁₋₅ alkyl and amino optionally mono-    or di-substituted by C₁₋₅ alkyl, aryl or aryl C₁₋₅ alkyl;

wherein c is a benzo ring fused to ring d which is a 5-7 memberedheterocyclic ring;

-   (iv) a 5 membered nitrogen containing heteroaryl or heterocyclic    ring optionally substituted by R¹ or R^(x);-   each R^(x) is chosen from C₁₋₆ alkyl or C₃₋₇ cycloalkyl each being    optionally substituted by C₁₋₃ alkyl and optionally partially or    fully halogenated, C₁₋₄ acyl, aroyl, C₁₋₄ alkoxy, which may    optionally be partially or fully halogenated, halogen, C₁₋₄    alkoxycarbonyl, carbocyclesulfonyl and —SO₂—CF₃;-   each J is independently chosen from C₁₋₁₀ alkyl and carbocycle each    optionally substituted by R^(b);-   R^(b) is chosen from hydrogen, C₁₋₅ alkyl, hydroxyC₁₋₅ alkyl, C₂₋₅    alkenyl, C₂₋₅ alkynyl, carbocycle, heterocycle, heteroaryl, C₁₋₅    alkoxy, C₁₋₅ alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅ dialkylamino,    C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, each    of the aforementioned are optionally partially or fully halogenated,    or R^(b) is chosen from C₁₋₅ alkylsulfonylamino, hydroxy, oxo,    halogen, nitro and nitrile;-   Q is a N or CR^(p);-   Y is >CR^(p)R^(v), —CR^(v)═C(R^(v))—, —O—, —N(R^(c))— or >S(O)_(m);-   each R^(c), R^(p), R^(v) and R^(y) are each independently hydrogen    or C₁₋₅ alkyl;-   X is >C═O, —CH₂—, —N(R^(c))—, —O— or —S—;-   Z₁ is —N— or >CH;-   Z₂ is —N(R^(c))—, —O— or >CH₂;-   R^(y) and R⁶ may combine to form a bridged group from the ring atoms    to which they are attached;-   each m independently 0, 1 or 2;-   w is 1-4;-   each R³, R⁴ and R⁵ are independently chosen from hydrogen, C₁₋₆    alkyl and halogen;-   R⁶ is chosen from-   O-J, —C(O)-J, —C(O)—O-J, J-S(O)_(m)—NR⁷R⁸—, J-S(O)_(m)—, —C(O)H,    —O-heterocycle as defined hereinbelow, —C(O)—NR⁷R⁸,    —C(O)—C(O)—NR⁷R⁸, —NR⁷R⁸, C₁₋₅ alkyl branched or unbranched, C₂₋₅    alkenyl, C₁₋₃ acyl, C₁₋₃ alkyl(OH), oxo, heterocycle selected from    morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl and    tetrahydrofuranyl, heteroaryl selected from pyridinyl, pyrimidinyl,    pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl,    furyl, isoxazolyl, thiazolyl, oxazolyl and isothiazolyl or aryl each    alkyl, alkenyl, acyl, heterocycle, heteroaryl and aryl are    optionally substituted by one to three hydroxy, oxo, C₁₋₃ alkyl,    C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, —NR⁷R⁸ or NR⁷R⁸—C(O)—;-   each R⁷ and R⁸ are independently hydrogen, phenyl C₀₋₃alkyl    optionally substituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino,    or R⁷ and R⁸ are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or unbranched    alkyl optionally substituted by C₁₋₄ alkoxy, hydroxy or mono or    diC₁₋₃ alkyl amino;-   or the pharmaceutically acceptable salts and/or isomers thereof.

In another embodiment there is provided a compound of the invention asdescribed immediately above and wherein:

-   Y is —O—, —S—, —NH—, —N(CH₂CH₃)— or —N(CH₃)—;-   if Ar is (i) then:-   R¹ is chosen from hydrogen, C₁₋₆ alkyl, C₃₋₇ cylcoalkyl, C₁₋₅    alkoxyl and nitrile, each of the aforementioned where possible are    optionally partially or fully halogenated or are optionally further    substituted with alkylsulfonylamino, alkoxyl, amino, alkylamino,    dialkylamino, hydroxyl, oxo, nitro or nitrile;-   R² is chosen from hydrogen, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, C₁₋₅    alkylC₁₋₅ alkoxy, hydroxy, hydroxy C₁₋₅ alkyl, oxo, C₁₋₅    alkylS(O)_(m)— and amino optionally mono- or di-substituted by C₁₋₅    alkyl, phenyl or phenyl C₁₋₅ alkyl;-   if Ar is (ii) then:-   R^(1′) is chosen from H, C₁₋₆ alkyl, J-S(O)_(m)—, J-S(O)_(m)—NH—,    J-NHS(O)_(m)—, C₁₋₅ alkoxyl, C₁₋₅ acyloxy, NH₂—C(O)—(CH₂)_(n)—,    heterocycle, heterocycleC₁₋₆ alkyl, heteroaryl and nitrile, each of    the aforementioned where possible are optionally partially or fully    halogenated or are optionally further substituted with    alkylsulfonylamino, alkoxyl, amino, alkylamino, dialkylamino,    hydroxyl, oxo, nitro and nitrile;-   R^(2′) is chosen from C₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—, C₁₋₅ alkyl    and C₁₋₅ alkoxy;-   or if Ar is (iii) then:-   ring d is a 5-6 membered heterocyclic ring.

In another embodiment, there are provided compounds of the formula (I)as described immediately above and wherein

-   Y is —N(CH₃)—;-   X is >C═O, —CH₂— or —O—;-   Q is CH;-   if Ar is (i) then:-   R¹ is chosen from hydrogen, C₁₋₆ alkyl or nitrile;-   R² is chosen from hydrogen, halogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, oxo or    C₁₋₅ alkylS(O)_(m)—;-   if Ar is (ii) then:-   R^(1′) is chosen from hydrogen, C₁₋₆ alkyl, C₁₋₅ alkylS(O)_(m)—,    C₁₋₅ alkylS(O)_(m)—NH—, C₁₋₅ alkoxyl, (C₁₋₅ alkyl)NH—C(O)—O—,    NH₂—C(O)—(CH₂)_(n)—, morpholino C₁₋₆ alkyl, heteroaryl chosen from    pyrazole, triazole, imidazole and tetrazole, and nitrile;-   R^(2′) is chosen from C₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—, C₁₋₅ alkyl    and C₁₋₅ alkoxy;-   or if Ar is (iii) then:-   ring d is a 5-6 membered heterocyclic ring such that rings c and d    fuse to form the following:

-   -   where each R is independently H or C₁₋₃ alkyl;

In yet another embodiment, there are provided compounds of the formula(I) as described in any of the embodiments shown above and wherein

-   J is chosen from C₁₋₁₀ alkyl, aryl and C₃₋₇ cycloalkyl each    optionally substituted by R^(b);-   R^(x) is independently chosen from C₁₋₆ alkyl which may optionally    be partially or fully halogenated, acetyl, aroyl, C₁₋₄ alkoxy, which    may optionally be partially or fully halogenated, halogen,    methoxycarbonyl, phenylsulfonyl and —SO₂—CF₃;-   R^(b) is chosen from hydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅    alkynyl, C₃₋₈ cycloalkylC₀₋₂ alkyl, aryl, C₁₋₅ alkoxy, C₁₋₅    alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅ dialkylamino, C₁₋₅ acyl,    C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, C₁₋₅    sulfonylamino, hydroxy, halogen, trifluoromethyl, nitro, nitrile,-   or R^(b) is chosen from heterocycle chosen from pyrrolidinyl,    pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,    thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,    tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,    1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,    tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene    sulfoxide, pentamethylene sulfone, tetramethylene sulfide,    tetramethylene sulfoxide and tetramethylene sulfone and heteroaryl    chosen from aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl,    thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl,    imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl,    quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,    benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl,    triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,    pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,    oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl; and-   R⁷ is hydrogen.

In another embodiment, there are provided compounds of the formula (I)as described immediately above and wherein

-   J is chosen from C₁₋₁₀ alkyl, phenyl, naphthyl and C₃₋₇ cycloalkyl    each optionally substituted by R^(b);-   each R³, R⁴ and R⁵ are hydrogen.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   R⁶ is present, and is chosen from-   O-J, —C(O)-J, —C(O)—O-J, J-S(O)_(m)—NR⁷R⁸—, J-S(O)_(m)—, —C(O)H,    —O-heterocycle as defined hereinbelow, —C(O)—NR⁷R⁸,    —C(O)—C(O)—NR⁷R⁸, —NR⁷R⁸, C₁₋₅ alkyl branched or unbranched, C₂₋₅    alkenyl, C₁₋₃ alkyl(OH), oxo, heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, pyrrolidinyl and tetrahydrofuranyl, and    aryl chosen from phenyl and naphthyl, each alkyl, alkenyl,    heterocycle and aryl are optionally substituted by one to three    hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino, amino    or C₁₋₅ alkoxycarbonyl;-   each R⁷ and R⁸ are independently hydrogen, phenylC₀₋₃alkyl    optionally substituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino,    or R⁷ and R⁸ are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or unbranched    alkyl optionally substituted by C₁₋₄ alkoxy, hydroxy or mono or    diC₁₋₃ alkyl amino.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   R⁶ is chosen from-   O-J, —C(O)-J, —C(O)—O-J, J-S(O)_(m)—NR⁷R⁸—, J-S(O)_(m)—, —C(O)H,    —O-heterocycle as defined hereinbelow, —C(O)—NR⁷R⁸,    —C(O)—C(O)—NR⁷R⁸, —NR⁷R⁸, C₁₋₅ alkyl branched or unbranched, C₂₋₅    alkenyl, C₁₋₃ alkyl(OH), oxo, heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, tetrahydropyranyl and pyrrolidinyl, and    phenyl, each alkyl, alkenyl, heterocycle and phenyl are optionally    substituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono    or diC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl;-   each R⁷ and R⁸ are independently hydrogen, phenylC₀₋₂alkyl    optionally substituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino,    or R⁷ and R⁸ are C₁₋₅ branched or unbranched alkyl optionally    substituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkyl amino.

In yet still another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

-   R⁶ is chosen from-   O-J, —C(O)-J, —C(O)—O-J, J-S(O)_(m)—NR⁷R⁸—, J-S(O)_(m)—, —C(O)H,    —O-heterocycle as defined hereinbelow, —C(O)—NR⁷R⁸,    —C(O)—C(O)—NR⁷R⁸, —NR⁷R⁸, C₁₋₅ alkyl branched or unbranched, C₂₋₅    alkenyl, C₁₋₃ alkyl(OH), oxo, heterocycle selected from morpholinyl,    piperazinyl, piperidinyl, tetrahydropyranyl and pyrrolidinyl, and    phenyl, each alkyl, alkenyl, heterocycle and phenyl are optionally    substituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono    or diC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   R^(y) and R⁶ optionally form a methylene bridged group from the ring    atoms to which they are attached.

For any of the above described embodiments, preferred embodiments whereAr is (i) include:

More preferred are

For any of the above described embodiments, preferred embodiments whereAr is (ii) include:

where R in these structures is C₁₋₅alkyl;

-   more preferred are

The following are representative compounds of the invention:

TABLE I

or the pharmaceutically acceptable salts and/or isomers thereof.

The following are representative compounds of the invention which can bemade from the general schemes and examples, and methods known in theart:

TABLE II

or the pharmaceutically acceptable salts and/or isomers thereof.

In all the compounds disclosed hereinabove in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

Of particular importance according to the invention are compounds offormula (I), for use as pharmaceutical compositions with ananti-cytokine activity.

The invention also relates to the use of a compound of formula (I), forpreparing a pharmaceutical composition for the treatment and/orprevention of a cytokine mediated disease or condition.

The invention also relates to pharmaceutical preparations, containing asactive substance one or more compounds of formula (I), or thepharmaceutically acceptable derivatives thereof, optionally combinedwith conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, 18F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

The invention includes the use of any compounds of described abovecontaining one or more asymmetric carbon atoms may occur as racematesand racemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereomers. Isomers shall be defined as being enantiomersand diastereomers. All such isomeric forms of these compounds areexpressly included in the present invention. Each stereogenic carbon maybe in the R or S configuration, or a combination of configurations.

Some of the compounds of formula (I) can exist in more than onetautomeric form. The invention includes methods using all suchtautomers.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₄alkoxy” is a C₁₋₄alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl and alkynyl groupsshall be understood as being branched or unbranched where structurallypossible and unless otherwise specified. Other more specific definitionsare as follows:

Carbocycles include hydrocarbon rings containing from three to twelvecarbon atoms. These carbocycles may be either aromatic or non-aromaticring systems. The non-aromatic ring systems may be mono- orpolyunsaturated. Preferred carbocycles include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certainterms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be usedinterchangeably.

The term “heterocycle” refers to a stable nonaromatic 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 memberedbicyclic heterocycle radical which may be either saturated orunsaturated. Each heterocycle consists of carbon atoms and one or more,preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure. Unless otherwise stated,heterocycles include but are not limited to, for example pyrrolidinyl,pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene sulfoxide,pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxideand tetramethylene sulfone.

The term “heteroaryl” shall be understood to mean an aromatic 5-8membered monocyclic or 8-11 membered bicyclic ring containing 1-4heteroatoms such as N,O and S. Unless otherwise stated, such heteroarylsinclude aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl,thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl,quinazolinyl, naphthyridinyl, indazolyl, triazolyl,pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl,pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl andimidazo[4,5-b]pyridinyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

In all alkyl groups or carbon chains one or more carbon atoms can beoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in defintions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

The term “aryl” as used herein shall be understood to mean aromaticcarbocycle or heteroaryl as defined herein. Each aryl or heteroarylunless otherwise specified includes it's partially or fully hydrogenatedderivative. For example, quinolinyl may include decahydroquinolinyl andtetrahydroquinolinyl, naphthyl may include it's hydrogenated derivativessuch as tetrahydranaphthyl. Other partially or fully hydrogenatedderivatives of the aryl and heteroaryl compounds described herein willbe apparent to one of ordinary skill in the art.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen. Forexample, for an —S—C₁₋₆ alkyl radical, unless otherwise specified, thisshall be understood to include —S(O)—C₁₋₆ alkyl and —S(O)₂—C₁₋₆ alkyl.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine, preferablyfluorine. The definitions “partially or fully halogenated”; partially orfully fluorinated; “substituted by one or more halogen atoms”, includesfor example, mono, di or tri halo derivatives on one or more carbonatoms. For alkyl, a non-limiting example would be —CH₂CHF₂, —CF₃ etc.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the inventive methodsdisclosed herein.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the formula (I).

Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic and organic acids and bases.Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric andbenzenesulfonic acids. Other acids, such as oxalic acid, while notthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsand their pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple chemical transformation, are modified to produce compoundsof the invention. Simple chemical transformations include hydrolysis,oxidation and reduction. Specifically, when a prodrug is administered toa patient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

General Synthetic Methods

The invention additionally provides for methods of making the compoundsof the formula (I). The compounds of the invention may be prepared bythe general methods and examples presented below, and methods known tothose of ordinary skill in the art. Further reference in this regard maybe made to U.S. Pat. Nos. 6,358,945, 6,492,393, 6,608,052, 6,765,009,and 6,743,788, US publication no. US 2003-0008868 A1. U.S. Pat. No.6,703,525 teaches additional methods for preparation of sulfonamideintermediates. Each of the aforementioned U.S. cases is incorporated inits entirety.

In all schemes, unless otherwise specified, Ar, Q, X, Y, Z₁, Z₂, n,R³-R⁶ and R^(y) in the formulas shown below shall have the meaningsdefined for these groups in the definition of the formula (I) of theinvention, described hereinabove. Intermediates used in the synthesesbelow are either commercially available or easily prepared by methodsknown to those skilled in the art. Reaction progress may be monitored byconventional methods such as thin layer chromatography (TLC).Intermediates and products may be purified by methods known in the art,including column chromatography, HPLC or recrystallization.

Compounds of the invention where X is a carbonyl group and Z₁═N may beprepared as described in Scheme I.

As illustrated in Scheme I an amine bearing Ar is coupled withcarboxylic acid III, where P is a protecting group, using standardcoupling conditions known in the art (see for example M. Bodanszky,1984, The Practice of Peptide Synthesis, Springer-Verlag). For example,one may couple III and II by treating with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)followed by 1-hydroxybenzotriazole hydrate (HOBT) in a suitable solventsuch as DMF. Removal of the protecting group P to provide V may beachieved by standard procedures known in the art. For example, if P is abenzyl group, it may be removed by treatment of IV with hydrogen gas inthe presence of a catalyst such as palladium on carbon in a suitablesolvent such as EtOH.

Conversion of V to a trifluoromethanesulfonate ester, for example bytreatment with N-phenyl-bis-(trifluoromethanesulfonimide) provides VI.This may then be reacted with the desired heterocycle VII (Z₁═NH) in thepresence of carbon monoxide and a palladium catalyst such as Pd(dppf)Cl₂in a suitable solvent such as DMF to provide the desired compound offormula I (X=a carbonyl group, Z₁═N), or a precursor which may bemodified by methods known in the art to provide the desired compound offormula I.

Compounds of formula I having X═CH₂ and Z₁═N may be prepared asillustrated in Scheme II.

As illustrated above, intermediate VIII is converted to the triflateester IX as described for the conversion of V to VI in Scheme I. AStille reaction of IX with tributyl(vinyl)tin in the presence of apalladium catalyst such as bis(triphenylphosphine)palladium(II) chlorideprovides the olefin intermediate X. The ester is then hydrolyzed toprovide carboxylic acid XI and coupled with ArNH₂, as described in thefirst step of Scheme I, to provide amide intermediate XII. Oxidation ofthe terminal olefin, for example by treatment with osmium tetroxide inthe presence of 4-methylmorpholine-N-oxide, followed by furtheroxidation of the intermediate diol with NaIO₄, provides aldehyde XIII.Reductive amination of XIII by treatment with amine heterocycle VIIunder reducing conditions, for example by treatment with NaBH(OAc)₃ inacetic acid, provides the desired compound of formula I (X═CH₂, Z₁═N) ora precursor which could be further modified to obtain the desiredcompound of formula I.

Compounds of formula I having X═—O—, —S—, or —N(R_(c))— and Z₁═CH may beprepared as illustrated in Scheme III

As illustrated above, intermediate VIII is reacted with a heterocyclebearing a sulfonic acid ester leaving group XIV, where R may be forexample a p-tolyl, 4-bromophenyl or trifluoromethyl group, to providethe ether intermediate XV. Hydrolysis of the ester provides carboxylicacid intermediate XVI which may be coupled with ArNH₂ as described inSchemes I and II to provide the desired compound of formula I (Z₁═CH) ora precursor which could be further modified to obtain the desiredcompound of formula I.

Scheme IV illustrates the preparation of compounds having X═CH₂ andZ₁═CH. Wittig reaction of a heterocyclic ketone XVII withmethyltriphenylphosphonium bromide in the presence of a strong base suchas butyl lithium provides olefin XVIII. Reaction of XVIII with triflateintermediate IX in the presence of a palladium catalyst such asPd(dppf)Cl₂ and a reducing agent such as 9-borabicyclo[3.3.1]nonyltrifluoromethanesulfonate (9-BBN) provides intermediate XIX. Hydrolysisof the ester to the carboxylic acid XX and coupling with ArNH₂ as in theschemes above provides the desired compound of formula I (X═CH₂, Z₁═CH)or a precursor which could be further modified to obtain the desiredcompound of formula I.

Several examples employing the methods found in Schemes I-IV aredescribed in the Synthetic Examples section below.

SYNTHETIC EXAMPLES Example 1 Synthesis of4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indole-7-carbonyl]-piperazine-1-carboxylicacid ethyl ester

To a solution ofN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (760 mg,2.65 mmol), 7-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (620 mg,2.20 mmol) and 1-hydroxybenzotriazole (HOBT, 376 mg, 2.65 mmol) in DMF(10 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC, 517 mg, 2.65 mmol), followed by4-(N,N-dimethylamino)pyridine (DMAP, 27 mg, 0.22 mmol). The mixture wasstirred under nitrogen for 3 days. Water was added. The mixture wasextracted with EtOAc, dried with Na₂SO₄ and concentrated. Purificationby silica gel chromatography using 10-50% (gradient) EtOAc-hexane gave850 mg (72%) of the desired amide.

A mixture of the above amide (850 mg, 1.59 mmol) and 10% Pd on carbon inEtOH (10 mL) and EtOAc (10 mL) was stirred under a H₂ filled balloon atroom temperature for 24 h. The mixture was then filtered throughdiatomaceous earth and concentrated. Purification by silica gelchromatography provided 700 mg (99%) of the desired hydroxyindole.

A solution of the above hydroxyindole (700 mg, 1.57 mmol) andN-phenyl-bis-(trifluoromethanesulfonimide) (567 mg, 1.57 mmol) in1,4-dioxane (10 mL) was heated at 70° C. overnight. AdditionalN-phenyl-bis-(trifluoromethanesulfonimide) (500 mg) was added and themixture was heated for an additional 4 h. TLC showed the reaction wascomplete. The mixture was cooled to room temperature and concentrated.Purification by silica gel chromatography provided 790 mg (87%) of thedesired triflate ester.

A solution of the above triflate ester (37 mg, 0.064 mmol), ethylN-piperazinocarboxylate (30 mg, 0.192 mmol) and Pd(dppf)Cl₂.CH₂CL₂ (10mg, 0.009 mmol) in DMF (degassed, 2 mL) was heated at 80° C. under CO (1atm) overnight. The mixture was then cooled to room temperature andconcentrated. Purification by silica gel chromatography provided 19 mg(48%) of the title compound as a white solid. ESI MS m/z 614.36 [M+H]⁺.

Example 2 Synthesis of4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 7-hydroxy-1-methyl-1H-indole-2-carboxylic acid ethylester (3.5 g, 16.0 mmol) and N-phenyltrifluoromethanesulfonimide (7.47g, 20.7 mmol) in anhydrous 1,4-dioxane (50 mL) was addedN,N-diisopropylethylamine (5.56 mL, 32 mmol). The resulting mixture washeated under nitrogen at 70° C. for 24 h. The mixture was then cooled toroom temperature and concentrated. The residue was purified by silicagel chromatography to give compound the desired triflate ester (3.14 g,56%) as a white solid.

To a suspension of lithium chloride (dried, 1.58 g, 37.3 mmol) in dryDMF (50 mL), under Ar, was added the above triflate ester (3.17 g, 9.02mmol), tributyl(vinyl)tin (2.7 mL, 9.02 mmol.),2,6-di-tert-butyl-4-methylphenol (237.6 mg, 1.06 mmol.) andbis(triphenylphosphine)palladium (II) chloride (191.6 mg, 0.280 mmol).The flask was evacuated and back-filled with argon 3 times. The reactionmixture was heated at 90° C. for 4 h and cooled to room temperature.Water was added. The mixture was extracted with EtOAc, dried with Na₂SO₄and concentrated. The residue was purified by silica gel chromatographyto give a mixture of the desired ethenylindole and tin impurities, total(3.39 g).

The crude product obtained from above was dissolved in THF (30 mL). Asolution of NaOH (1N, 15 mL, 15 mmol) was added. The resultingsuspension was stirred at room temperature for 3 h. Water (40 mL) addedand the bulk of organics were removed under vacuum. The aqueous layerwas washed with Et₂O and acidified to pH about 2. The mixture wasextracted with EtOAc (3×40 mL). The organic extracts were combined andwashed with brine, dried over MgSO₄, and concentrated to give thedesired carboxylic acid as a white solid (1.3 g, 6.46 mmol, yield 72.0%for two steps).

To a solution of the above carboxylic acid (1.6 g, 8.2 mmol) in DMF (80mL) was addedN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (2.21 g,8.14 mmol.),O-(7-azobenzotriazol-1-yl)-N,N,N′,N′-tetrauroniumhexafluorophosphate(HATU, 3.15 g, 8.260 mmol), 2.56 mL of triethylamine (2.56 mL, 18.4mmol), and 1-hydroxybenzotriazole (HOAT, 307.4 mg, 2.240 mmol). Theresulting mixture was stirred at room temperature overnight. Thereaction mixture was then diluted with EtOAc, washed with water, driedwith sodium sulfate and concentrated. The crude product was purified bysilica gel chromatography to afford 2.12 g (56.8%) of the desiredethenylindole amide.

To a solution of the above ethenylindole amide (2.3 g, 5.06 mmol) inacetone (90 mL) and water (30 mL) was added osmium tetraoxide (2.5 wt %in t-BuOH, 690 μL, 0.230 mmol) and 4-methylmorpholine N-oxide (2.99 g,25.5 mmol). The resulting yellowish mixture was stirred for 2 h. Thereaction was quenched by addition of Na₂SO₃ (4.6 g) in water (35 mL).The mixture was then extracted with dichloromethane, washed with brine,dried with sodium sulfate and concentrated to afford (2.34 g, 94.6%) ofthe desired diol intermediate, which was directly used in the nextreaction.

To a suspension of silica gel (7.5 g) in dichloromethane (45 mL) wasadded a solution of NaIO₄ (525 mg, 2.455 mmol) in H₂O (4 mL) dropwisewith vigorously stirring. A solution of the diol intermediate from above(550 mg, 1.123 mmol) in dichloromethane (5 mL) was added. The mixturewas stirred vigorously for 2 h when TLC indicated that the reaction wascomplete. The reaction mixture was then filtered and the silica gel waswashed with several portions of dichloromethane. The combined filtrateswere dried over Na₂SO₄ and concentrated to give the desired aldehyde(455 mg, 87.6%) as a yellowish foam.

To a solution of the above aldehyde (600 mg, 1.31 mmol) and tert-butylN-piperazinocarboxylate (2.44 g, 13.1 mmol) in dichloroethane (48 mL)was added acetic acid (1.5 mL). The mixture was stirred at roomtemperature for 30 min. To this mixture was then added sodiumtriacetoxyborohydride (1.1 μg, 5.24 mmol). The mixture was stirred atroom temperature overnight and quenched with saturated NaHCO₃. Themixture was then extracted with dichloromethane, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel chromatography togive 495 mg (60%) of the title compound. ESI MS m/z 628.69 [M+H]⁺.

Example 3 Synthesis of4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylicacid ethyl ester

To a solution of 7-formyl-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (seeExample 2, 30 mg, 0.066 mmol) and ethyl N-piperazinocarboxylate (104 mg,0.66 mmol) in dichloroethane (2 mL) was added acetic acid (0.1 mL). Themixture was stirred at room temperature for 4 h. Sodiumtriacetoxyborohydride (35 mg, 0.156 mmol) was then added to the reactionmixture. The reaction was stirred overnight at room temperature and thenquenched with saturated NaHCO₃ solution. The mixture was then extractedwith EtOAc and dichloromethane in sequence, dried over Na₂SO₄ andconcentrated. The residue was purified by preparative-TLC, eluting withEtOAc-hexane, 1:1, providing 15 mg (38%) of the title compound. ESI MSm/z 600.37 [M+H]⁺.

Example 4 Synthesis of7-(4-aminooxalyl-piperazin-1-ylmethyl)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

To a solution of4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester (87 mg, 0.139 mmol) in MeOH (1 mL) was addedconcentrated HCl (50 μL). The mixture heated to reflux for 2 h, cooledto room temperature and basified with NaHCO₃ (sat.) to pH˜9. The mixturewas then extracted with EtOAc several times. The combined organicextracts were washed with brine, dried over MgSO₄ and concentrated togive the desired deprotected piperazine as a white foam (87 mg). Theproduct was characterized by ¹H NMR and mass spectroscopy.

To a solution of oxamic acid (10.24 mg, 0.115 mmol) in DMF (1 mL) wasadded HATU (43.7 mg, 0.115 mmol), HOAT (7.83 mg, 0.058 mmol) anddiisopropylethylamine (40 μl, 0.230 mmol). After 10 min, the abovedeprotected piperazine (13 mg, 0.025 mmol) was added. The mixture wasstirred at room temperature for 3 days. The reaction mixture was thendiluted with EtOAc, washed with NaHCO₃ (sat.) and brine in sequence. Theorganic layer was dried over MgSO₄ and concentrated. The crude productwas purified by silica gel chromatography to give 13 mg of the titlecompound as a white foam, yield 87%.

ESI MS m/z 599.65 [M+H]⁺.

Example 5 Synthesis of7-(4-ethylcarbamoyl-piperazin-1-ylmethyl)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

To a solution of tert-butyl piperazinocarboxylate (1 g, 5.4 mmol) indichloromethane (5 mL), ethyl isocyanate (763 mg, 10.7 mmol) was addeddropwise at 0° C. The mixture was stirred for 30 min and concentrated toremove solvent and excess ethyl isocyanate, providing 1.4 g (100%) ofthe desired urea as a white solid.

To a solution of the above urea (170 mg, 0.66 mmol) in dichloromethane(2 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirredat room temperature for 1 h and concentrated to give the TFA salt of thedesired piperazine urea (226 mg) as a colorless oil. The product wascharacterized by ¹H NMR and used as such in later reactions.

The title compound was prepared from the above piperazine urea salt and7-formyl-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide by usingthe same reductive amination procedure described in Example 2, yield67.5%. ESI MS m/z 598.76 [M+H]⁺.

Example 6 Synthesis of7-(4-dimethylcarbamoyl-piperazin-1-ylmethyl)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

Piperazine-1-carboxylic acid 2,2,2-trichloro-ethyl ester and7-formyl-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide werereacted under the reductive amination conditions described in Example 2to provide the desired4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylicacid 2,2,2-trichloro-ethyl ester.

To a solution of the above ester (25 mg, 0.036 mmol) in DMSO (1 mL) wasadded 2M Me₂NH-THF (1 mL) and the mixture was heated in a pressure tubeat 100° C. for 3 days. The mixture was then cooled to room temperature,diluted with water, and extracted several times with EtOAc. The combinedorganic layers were washed with saturated NaCl, dried over MgSO₄ andconcentrated. Purification by silica gel chromatography provided 9 mg ofthe title compound, yield 42%. ESI MS m/z 599.63 [M+H]⁺.

Example 7 Synthesis of4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-yloxy]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of 1,4-diazabicyclo[2.2.2]octane (1.65 g, 14.7 mmol) andtert-butyl 4-hydroxypiperidinecarboxylate (2.46 g, 12.24 mmol) in drytoluene (10 mL) was added a solution of 4-bromobenzosulfonyl chloride(3.13 g, 12.24 mmol.) in toluene (10 mL), dropwise at 0° C. The mixturewas stirred for 2 h, during which white precipitate formed. The mixturewas then diluted with EtOAc (100 mL) and filtered. The filtrate waswashed with water, 10% citric acid and saturated NaCl solution insequence and dried with Na₂SO₄. Removal of solvent gave 4.88 g (95%) of4-(4-bromo-benzenesulfonyloxy)-piperidine-1-carboxylic acid tert-butylester as a white solid.

To a solution of 7-hydroxy-1-methyl-1H-indole-2-carboxylic acid ethylester (515 mg, 2.3 mmol) in DMF (15 mL) was added Cs₂CO₃ (1.3 g, 3.99mmol) followed by the above tert-butyl ester (1.1 g, 2.6 mmol). Themixture was heated under nitrogen at 60° C. for 2 h. After the mixturewas cooled to room temperature, the bulk of DMF was removed. Water (10mL) was added. The mixture was extracted with EtOAc, dried over Na₂SO₄and concentrated. Purification by silica gel chromatography gave 550 mg(53%) of desired ether as a white solid.

To a solution of the above ether (885 mg, 2.2 mmol) in MeOH (10 mL) wasadded 10% KOH solution in 9:1 MeOH—H₂O (1.5 mL). The mixture was heatedat 70° C. for 6 h. The mixture was cooled to room temperature andconcentrated. The residue was re-dissolved in water (5 mL) and acidifiedto about pH 4 with 10% citric acid. The precipitate was collected byfiltration and dried under vacuum to give 760 mg (92%) of the desiredindole carboxylic acid.

To a solution of the above carboxylic acid (380 mg, 1.02 mmol),N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (350 mg,1.29 mmol), HOBt (190 mg, 1.34 mmol) in DMF (10 mL) was added EDC (250mg, 1.28 mmol), followed by DMAP (20 mg, 0.16 mmol). The mixture wasstirred under nitrogen for three days. After the bulk of DMF wasremoved, water (10 mL) was added. The mixture was extracted with EtOAc,dried with Na₂SO₄ and concentrated. Silica gel chromatography provided415 mg (65%) the title compound. ESI MS m/z 629.70 [M+H]⁺.

Example 8 Synthesis of4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-yloxy]-piperidine-1-carboxylicacid ethyl ester

To a solution of4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-yloxy]-piperidine-1-carboxylicacid tert-butyl ester (160 mg, 0.254 mmol) (Example 7) indichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL). Themixture was stirred at room temperature overnight and concentrated. Thecrude piperidine intermediate thus obtained was dried under vacuum anddirectly used in later reactions.

To a solution of the above piperidine intermediate (34 mg, 0.064 mmol)and triethylamine (0.1 mL, 1.0 mmol) in dichloromethane (1 mL) was addedethyl chloroformate (10 μL, 0.092 mmol) at 0° C. The mixture was stirredat 0° C. for 1 h and concentrated. Purification by preparative TLC gave25 mg (65%) of the title compound.

ESI MS m/z 601.42 [M+H]⁺.

Example 9 Synthesis of1-methyl-7-(4-propionyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-phenyl)-amide

To a solution of 1-methyl-7-vinyl-1H-indole-2-carboxylic acid (53 mg,0.26 mmol) in DMF (3 mL) was added 5-tert-butyl-o-anisidine (47 mg, 0.26mmol),O-(7-azobenzotriazol-1-yl)-N,N,N′,N′-tetrauroniumhexafluorophosphate(HATU, 100 mg, 0.26 mmol), triethylamine (80 μL, 0.82 mmol), and1-hydrxybenzotriazol (HOAT, 10 mg, 0.07 mmol). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was thendiluted with EtOAc, washed with water, dried with sodium sulfate andconcentrated. The crude product was purified Prep-TLC to afford 53 mg(56%) of the desired amide intermediate.

To a solution of the above amide intermediate (53 mg, 0.15 mmol) inacetone (2 mL) and water (0.1 mL) was added osmium tetraoxide (2.5 wt %in t-BuOH, 16 μl, 0.01 mmol) and 4-methylmorpholine N-oxide (68 mg, 0.58mmol). The resulting yellowish mixture was stirred for 2 h. The reactionwas quenched by addition of Na₂SO₃ (100 mg) in water (0.5 mL). Themixture was then extracted with dichloromethane, washed with brine,dried with sodium sulfate and concentrated. The residue was purified bypreparative TLC using 5% MeOH-dichloromethane to afford 49 mg (82%) ofthe diol intermediate.

To a suspension of silica gel (0.75 g) in dichloromethane (5 mL) wasadded a solution of NaIO₄ (62 mg, 0.29 mmol) in H₂O (0.4 mL) dropwisewith vigorously stirring. A solution of the diol intermediate from above(49 mg, 0.12 mmol) in dichloromethane (0.5 mL) was added. The mixturewas stirred vigorously for 2 h when TLC indicated that the reaction wascomplete. The reaction mixture was then filtered and the silica gel waswashed with dichloromethane (15 mL). The combined filtrates were driedover Na₂SO₄ and concentrated to give the desired aldehyde intermediate(35 mg, 80%) as a yellowish foam.

To a solution of the above aldehyde intermediate (35 mg, 0.1 mmol) and1-propionylpiperazine (142 mg, 1.0 mmol) in dichloroethane (0.7 mL) wasadded acetic acid (0.15 mL). The mixture was stirred at room temperaturefor 1.5 hr. To this mixture was then added sodium triacetoxyborohydride(106 mg, 0.5 mmol). The mixture was stirred at room temperatureovernight and quenched with sat NaHCO₃. The mixture was then extractedwith dichloromethane, dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel chromatography to give 45 mg (92%) of thetitle compound.

ESI MS m/z 490.65 [M+H]⁺.

Example 10 Synthesis of4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-1-carboxylicacid tert-butyl ester

To a mixture of methyltriphenylphosphonium bromide (14.3 g, 40 mmol) andanhydrous THF (50 ml) at −78° C. was added dropwise tert-butyllithium(9.6 mL of a 2.5 M solution in hexane, 24 mmol). After 10 min ofstirring, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butylester (4 g, 20 mmol) in THF (15 mL) was added. The mixture was allowedto warm slowly to −20° C. The reaction was quenched by addition ofsaturated NH₄Cl solution. The product was extracted with ethyl etherthree times. The organics were combined and washed with water and brine,dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby column chromatography (10% EtOAc/hexane) to yield 3 g (76% yield) ofthe desired olefin intermediate.

To a sample of the above olefin intermediate (168 mg, 0.85 mmol) wasadded 9-BBN (1.7 mL of 0.5 M solution in THF). The resulting solutionwas refluxed for 1 h. After cooling to room temperature, the solutionwas added to a mixture of the triflate (300 mg, 0.85 mmol), Pd(dppf)Cl₂(complex with dichloromethane, 21 mg, 0.026 mmol), DMF (4 mL), water(0.4 mL), and K₂CO₃ (950 mg). The resulting mixture was heated at 60° C.for 4 h. The mixture was cooled to room temperature, poured into waterand extracted with EtOAc. The combined organic layers were combined,washed with brine, dried with Na₂SO₄, and concentrated to give a crudeoil which was purified by a short plug of silica gel to afford 0.34 g of7-(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-1-methyl-1H-indole-2-carboxylicacid ethyl ester.

The above indole-2-carboxylic acid ethyl ester intermediate wasdissolved in THF/MeOH/H₂O (3:1:1) and 1 mL of 1N KOH solution. Themixture was heated at 60° C. for 4 h. The mixture was then cooled to 0°C. and acidified with 10% citric acid to about pH 4. The mixture wasextracted with EtOAc, dried and concentrated to afford 0.32 g of theindole-2-carboxylic acid intermediate.

To a solution of the above indole carboxylic acid intermediate (168 mg,0.45 mmol), N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide(315 mg, 1.2 mmol) and HOBt (157 mg, 1.16 mmol) in DMF (10 mL) was addedEDC (222 mg, 1.16 mmol), followed by DMAP (18 mg, 0.16 mmol). Themixture was stirred at room temperature overnight. The bulk of thesolvent was removed, and residue was suspended in water. The mixture wasextracted with EtOAc, dried with Na₂SO₄ and concentrated. Silica gelchromatography to afford 170 mg (60% yield) of the title compound as awhite foam.

ESI MS m/z 627.34 [M+H]⁺.

Example 11 Synthesis of1-Methyl-7-(1-propionyl-piperidin-4-ylmethyl)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

To a solution of4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-1-carboxylicacid tert-butyl ester (Example 9) (50 mg, 0.08 mmol) in 1 mL CH₂CL₂ at0° C. was added TFA(0.05 mL). The solution was stirred at 0° C. to roomtemperature for 4 h. The mixture was then concentrated. The crudeunprotected piperidine intermediate was used directly used in laterreactions.

At 0° C., under N₂, triethylamine (0.12 mL, 1.14 mmol) was added to asolution of the above piperidine intermediate (0.08 mmol) in CH₂Cl₂ (1mL). Propionyl chloride (10 μL, 0.11 mmol) was added. The mixture wasstirred at 0° C. for 1 h, quenched with MeOH (1 mL) and concentrated.The residue was purified by preparative TLC to afford 20 mg (60% yield)of the title compound as a white foam. ESI MS m/z 583.37 [M+H]⁺.

Table 3 illustrates additional compounds of the invention which can bemade by methods analogous to those described above.

TABLE 3 Example Number Structures 12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

24

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

Methods of Use

In accordance with the invention, there are provided novel methods ofusing the compounds of the formula (I). The compounds disclosed thereineffectively block inflammatory cytokine production from cells. Theinhibition of cytokine production is an attractive means for preventingand treating a variety of cytokine mediated diseases or conditionsassociated with excess cytokine production, e.g., diseases andpathological conditions involving inflammation. Thus, the compounds areuseful for the treatment of diseases and conditions as described in theBackground section, including the following conditions and diseases:

osteoarthritis, atherosclerosis, contact dermatitis, bone resorptiondiseases, reperfusion injury, asthma, multiple sclerosis, Guillain-Barresyndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versushost disease, systemic lupus erythematosus and insulin-dependentdiabetes mellitus, rheumatoid arthritis, toxic shock syndrome,Alzheimer's disease, diabetes, inflammatory bowel diseases, acute andchronic pain as well as symptoms of inflammation and cardiovasculardisease, stroke, myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, syndromes associated withhemodialysis, leukopherisis, granulocyte transfusion associatedsyndromes, and necrotizing entrerocolitis, complications includingrestenosis following percutaneous transluminal coronary angioplasty,traumatic arthritis, sepsis, chronic obstructive pulmonary disease andcongestive heart failure. The compounds of the invention may also beuseful for anticoagulant or fibrinolytic therapy (and the diseases orconditions related to such therapy) as described in US publication no.U.S. 2004-0033222 A1.

The compounds of the invention are also p38 Map kinase inhibitors, andtherefore will be useful for treating oncological diseases and othercytokine mediated diseases and conditions related to p38 Map kinase asknown in the art. Methods of assaying for p38 Map kinase activity can beperfomed by known methods. See for example Branger, J. et al, TheJournal of Immunology, (2002), 168: 4070-4077, and the 46 referencescited therein, each incorporated herein by reference in their entirety.Oncological diseases include but are not limited to solid tumors, suchas cancers of the breast, respiratory tract, brain, reproductive organs,digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma and mesothelioma.

Examples of brain cancers include, but are not limited to brain stem,optic and hypophtalmic glioma, cerebella and cerebral astrocytoma,medulloblastoma, ependymoma, as well as pituitary, neuroectodermal andpineal tumor.

Examples of peripheral nervous system tumors include, but are notlimited to neuroblastoma, ganglioneuroblastoma, and peripheral nervesheath tumors.

Examples of tumors of the endocrine and exocrine system include, but arenot limited to thyroid carcinoma, adrenocortical carcinoma,pheochromocytoma, and carcinoid tumors.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer.

Tumors of the female reproductive organs include, but are not limited toendometrial, cervical, ovarian, vaginal, and vulvar cancer, as well assarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallblader, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),hepatoblastoma, cholangiocarcinoma (intrahepatic bile duct carcinoma),and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, Hodgkins lymphoma, cutaneous T-cell lymphoma,and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, Ewings sarcoma, malignant fibrous histiocytoma,lymphosarcoma, angiosarcoma, and rhabdomyosarcoma. Leukemias include,but are not limited to acute myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia,and hairy cell leukemia.

Plasma cell dyscrasias include, but are not limited to multiple myeloma,and Waldenstrom's macroglobulinemia.

These disorders have been well characterized in man, but also exist witha similar etiology in other mammals, and can be treated bypharmaceutical compositions of the present invention.

For therapeutic use, the compounds may be administered in anyconventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

The compounds may be administered alone or in combination with adjuvantsthat enhance stability of the inhibitors, facilitate administration ofpharmaceutic compositions containing them in certain embodiments,provide increased dissolution or dispersion, increase inhibitoryactivity, provide adjunct therapy, and the like, including other activeingredients. Advantageously, such combination therapies utilize lowerdosages of the conventional therapeutics, thus avoiding possibletoxicity and adverse side effects incurred when those agents are used asmonotherapies. The above described compounds may be physically combinedwith the conventional therapeutics or other adjuvants into a singlepharmaceutical composition. Reference is this regard may be made toCappola et al.: U.S. Pat. No. 6,565,880 and U.S. application Ser. No.10/214,782, each incorporated by reference herein in their entirety.Advantageously, the compounds may then be administered together in asingle dosage form. In some embodiments, the pharmaceutical compositionscomprising such combinations of compounds contain at least about 5%, butmore preferably at least about 20%, of a compound of formula (I) (w/w)or a combination thereof. The optimum percentage (w/w) of a compound ofthe invention may vary and is within the purview of those skilled in theart. Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

As mentioned above, dosage forms of the compounds described hereininclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 1-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. Referencein this regard may also be made to US publication no. U.S. 2003-0118575A1. As the skilled artisan will appreciate, lower or higher doses may berequired depending on particular factors. For instance, specific dosageand treatment regimens will depend on factors such as the patient'sgeneral health profile, the severity and course of the patient'sdisorder or disposition thereto, and the judgment of the treatingphysician.

Biological Assays

Inhibition of TNF Production in THP Cells

The inhibition of cytokine production can be observed by measuringinhibition of TNFα in lipopolysaccharide stimulated THP cells (forexample, see W. Prichett et al., 1995, J Inflammation, 45, 97). Allcells and reagents were diluted in RPMI 1640 with phenol red andL-glutamine, supplemented with additional L-glutamine (total: 4 mM),penicillin and streptomycin (50 units/ml each) and fetal bovine serum(FBS, 3%) (GIBCO, all conc. final). Assay was performed under sterileconditions; only test compound preparation was nonsterile. Initial stocksolutions were made in DMSO followed by dilution into RPMI 1640 2-foldhigher than the desired final assay concentration. Confluent THP.1 cells(2×10⁶ cells/ml, final conc.; American Type Culture Company, Rockville,Md.) were added to 96 well polypropylene round bottomed culture plates(Costar 3790; sterile) containing 125 μl test compound (2 foldconcentrated) or DMSO vehicle (controls, blanks). DMSO concentration didnot exceed 0.2% final. Cell mixture was allowed to preincubate for 30min, 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS; 1μg/ml final; Siga L-2630, from E. coli serotype 0111.B4; stored as 1mg/ml stock in endotoxin screened distilled H₂O at −80° C.). Blanks(unstimulated) received H₂O vehicle; final incubation volume was 250 μl.Overnight incubation (18-24 h) proceeded as described above. Assay wasterminated by centrifuging plates 5 min, room temperature, 1600 rpm(400×g); supernatants were transferred to clean 96 well plates andstored −80° C. until analyzed for human TNFα by a commercially availableELISA kit (Biosource #KHC3015, Camarillo, Calif.). Data was analyzed bynon-linear regression (Hill equation) to generate a dose response curveusing SAS Software System (SAS institute, Inc., Cary, N.C.). Thecalculated IC₅₀ value is the concentration of the test compound thatcaused a 50% decrease in the maximal TNFα production.

Preferred compounds have an IC₅₀<1 uM in this assay.

Inhibition of Other Cytokines

By similar methods using peripheral blood monocytic cells, appropriatestimuli, and commercially available ELISA kits (or other method ofdetection such as radioimmunoassay), for a particular cytokine,inhibition of IL-1beta, GM-CSF, IL-6 and IL-8 can be demonstrated forpreferred compounds (for example, see J. C. Lee et al., 1988, Int. J.Immunopharmacol., 10, 835).

All references cited in this application are incorporated herein byreference in their entirety.

1. A compound of the formula (I)

wherein: n is 2; Ar is ring (ii):

wherein R^(1′) is chosen from hydrogen, J-S(O)_(m)—, J-S(O)_(m) —NH—,J-NHS(O)_(m)—, C₁₋₆ alkyl, C₃₋₇ cylcoalkyl, C₁₋₅ alkoxyl or C₃₋₇cycloalkoxyl, C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₂₋₅alkenyl, C₂₋₅ alkynyl, heterocycle, heterocycleC₁₋₆ alkyl, heteroaryl,heteroarylC₁₋₆ alkyl and nitrile, each of the aforementioned wherepossible are optionally partially or fully halogenated or are optionallyfurther substituted with alkylsulfonylamino, alkoxyl, amino, alkylamino,dialkylamino, hydroxyl, oxo, nitro or nitrile; R²′, is chosen fromnitrile, J-S(O)_(m)-, J-O—C(O)—O—, NH₂—C(O)—(CH₂)_(w)—, H, halogen, C₁₋₅alkyl, C₁₋₅ alkoxy, C₁₋₅ alkylC₁₋₅ alkoxy, hydroxy, hydroxy C₁₋₅ alkyland amino optionally mono- or di-substituted by C₁₋₅ alkyl, aryl or arylC₁₋₅ alkyl; each R^(x) is chosen from C₁₋₆ alkyl or C₃₋₇ cycloalkyl eachbeing optionally substituted by C₁₋₃ alkyl and optionally partially orfully halogenated, C₁₋₄ acyl, aroyl, C₁₋₄ alkoxy, which may optionallybe partially or fully halogenated, halogen, C₁₋₆ alkoxycarbonyl,carbocyclesulfonyl and —SO₂—CF₃; each J is independently chosen fromC₁₋₁₀ alkyl and carbocycle each optionally substituted by R^(b); R^(b)is chosen from hydrogen, C₁₋₅ alkyl, hydroxyC₁₋₅ alkyl, C₂₋₅ alkenyl,C₂₋₅ alkynyl, carbocycle, heterocycle, heteroaryl, C₁₋₅ alkoxy, C₁₋₅alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅ dialkylamino, C₁₋₅ acyl, C₁₋₅alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅ acylamino, each of the aforementionedare optionally partially or fully halogenated, or R^(b) is chosen fromC₁₋₅ alkylsulfonylamino, hydroxy, oxo, halogen, nitro and nitrile; Q isa N or CR^(p); Y is —N(R^(c)); each R^(c) and R^(p) are eachindependently hydrogen or C₁₋₅ alkyl; X is >C═O, —CH₂—, —N(R^(c))—, —O—or —S—; Z₁ is —N; Z₂ is —N(R^(c)); each m independently 0, 1 or 2; w is1-4; each R³, R⁴ and R⁵ are independently chosen from hydrogen, C₁₋₆alkyl and halogen; R⁶ is chosen from O-J, —C(O)-J, —C(O)—O-J,J-S(O)_(m)—NR⁷R⁸—, J-S(O)_(m)—, —C(O)H, —O-heterocycle as definedhereinbelow, —C(O)—NR⁷R⁸, —C(O)—C(O)—NR⁷R⁸, —NR⁷R⁸, C₁₋₅ alkyl branchedor unbranched, C₂₋₅ alkenyl, C₁₋₃ acyl, C₁₋₃ alkyl(OH), oxo, heterocycleselected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl andtetrahydrofuranyl, heteroaryl selected from pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl,isoxazolyl, thiazolyl, oxazolyl and isothiazolyl or aryl each alkyl,alkenyl, acyl, heterocycle, heteroaryl and aryl are optionallysubstituted by one to three hydroxy, oxo, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₅alkoxycarbonyl, —NR⁷R⁸ or NR⁷R⁸—C(O)—; each R⁷ and R⁸ are independentlyhydrogen, phenylC₀₋₃ alkyl optionally substituted by halogen, C₁₋₃ alkylor diC₁₋₅ alkyl amino, or R⁷ and R⁸ are C₁₋₂ acyl, benzoyl or C₁₋₅branched or unbranched alkyl optionally substituted by C₁₋₄ alkoxy,hydroxy or mono or diC₁₋₃ alkyl amino; or the pharmaceuticallyacceptable salts thereof.
 2. The compound according to claim 1 andwherein: Y is —NH—, —N(CH₂CH₃)— or —N(CH₃)—; R¹′ is chosen from H, C₁₋₆alkyl, J-S(O)_(m)—, J-S(O)_(m)—NH—, J-NHS(O)_(m)—, C₁₋₅ alkoxyl, C₁₋₅acyloxy, NH₂—C(O)—(CH₂)_(w)—, heterocycle, heterocycleC₁₋₆ alkyl,heteroaryl and nitrile, each of the aforementioned where possible areoptionally partially or fully halogenated or are optionally furthersubstituted with alkylsulfonylamino, alkoxyl, amino, alkylamino,dialkylamino, hydroxyl, oxo, nitro and nitrile; and R²′ is chosen fromC₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—, C₁₋₅ alkyl and C₁₋₅ alkoxy.
 3. Thecompound according to claim 2 and wherein: Y is —N(CH₃)—; X is >C═O,—CH₂— or —O—; Q is CH; R¹′ is chosen from hydrogen, C₁₋₆ alkyl, C₁₋₅alkylS(O)_(m)—, C₁₋₅ alkylS(O)_(m)—NH—, C₁₋₅ alkoxyl, (C₁₋₅alkyl)NH—C(O)—O—, NH₂—C(O)—(CH₂)_(n)—, morpholino C₁₋₆ alkyl, heteroarylchosen from pyrazole, triazole, imidazole and tetrazole, and nitrile;and R²′ is chosen from C₁₋₅ alkylS(O)_(m)—, J-O—C(O)—O—, C₁₋₅ alkyl andC₁₋₅ alkoxy.
 4. The compound according to claim 3 and wherein: J ischosen from C₁₋₁₀ alkyl, aryl and C₃₋₇ cycloalkyl each optionallysubstituted by R^(b); R^(x) is independently chosen from C₁₋₆ alkylwhich may optionally be partially or fully halogenated, acetyl, aroyl,C₁₋₄ alkoxy, which may optionally be partially or fully halogenated,halogen, methoxycarbonyl, phenylsulfonyl and —SO₂—CF₃; R^(b) is chosenfrom hydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, C₃₋₈cycloalkylC₀₋₂ alkyl, aryl, C₁₋₅ alkoxy, C₁₋₅ alkylthio, amino, C₁₋₅alkylamino, C₁₋₅ dialkylamino, C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅acyloxy, C₁₋₅ acylamino, C₁₋₅ sulfonylamino, hydroxy, halogen,trifluoromethyl, nitro, nitrile, or R^(b) is chosen from heterocyclechosen from pyrrolidinyl, pyrrolinyl, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxalanyl,piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrofuranyl, 1,3-dioxolanone, 1,3- dioxanone, 1,4-dioxanyl,piperidinonyl, tetrahydropyrimidonyl, pentamethylene sulfide,pentamethylene sulfoxide, pentamethylene sulfone, tetramethylenesulfide, tetramethylene sulfoxide and tetramethylene sulfone andheteroaryl chosen from aziridinyl, thienyl, furanyl, isoxazolyl,oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl,quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl,triazolyl, pyrazolo[3,4 -b]pyrimidinyl, purinyl,pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl.
 5. The compoundaccording to claim 4 and wherein: J is chosen from C₁₋₁₀ alkyl, phenyl,naphthyl and C₃₋₇ cycloalkyl each optionally substituted by R^(b); eachR³, R⁴ and R⁵ are hydrogen.
 6. The compound according to claim 5 andwherein: R⁶ is present, and is chosen from O-J, —C(O)-J, —C(O)—O-J,J-S(O)_(m)—NR⁷R⁸—, J-S(O)_(m)—, —C(O)H, —O—-heterocycle as definedhereinbelow, —C(O)—NR⁷R⁸, —C(O)—C(O)—NR⁷R⁸, —NR⁷R⁸, C₁₋₅ alkyl branchedor unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), oxo, heterocycle selectedfrom morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl andtetrahydrofuranyl, and aryl chosen from phenyl and naphthyl, each alkyl,alkenyl, heterocycle and aryl are optionally substituted by one to threehydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino, amino orC₁₋₅ alkoxycarbonyl.
 7. The compound according to claim 6 and wherein:R⁶ is chosen from O-J, —C(O)-J, —C(O)—O-J, J-S(O)_(m)—NR⁷R⁸—,J-S(O)_(m)—, —C(O)H, —O-heterocycle as defined hereinbelow, —C(O)—NR⁷R⁸,—C(O)—C(O)—NR⁷R⁸, —NR⁷R⁸, C₁₋₅ alkyl branched or unbranched, C₂₋₅alkenyl, C₁₋₃ alkyl(OH), oxo, heterocycle selected from morpholinyl,piperazinyl, piperidinyl, tetrahydropyranyl and pyrrolidinyl, andphenyl, each alkyl, alkenyl, heterocycle and phenyl are optionallysubstituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono ordiC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl; each R⁷ and R⁸ areindependently hydrogen, phenylC₀₋₂ alkyl optionally substituted byhalogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, or R⁷ and R⁸ are C₁₋₅branched or unbranched alkyl optionally substituted by C₁₋₄ alkoxy,hydroxy or mono or diC₁₋₃ alkyl amino.
 8. The compound according toclaim 7 and wherein: R⁶ is chosen from O-J, —C(O)-J, —C(O)—O-J,J-S(O)_(m)—NR⁷R⁸—, J-S(O)_(m)—, —C(O)H, —O-heterocycle as definedhereinbelow, —C(O)—NR⁷R⁸, —C(O)—C(O)—NR⁷R⁸, —NR⁷R⁸, C₁₋₅ alkyl branchedor unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), oxo, heterocycle selectedfrom morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl andpyrrolidinyl, and phenyl, each alkyl, alkenyl, heterocycle and phenylare optionally substituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃alkoxy, mono or diC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl.
 9. Thecompound according to claim 1 wherein Ar is:

where R in these structures is C₁₋₅alkyl.
 10. The compound according toclaim 9 wherein Ar is:


11. A pharmaceutical composition containing a pharmaceutically effectiveamount of a compound according to claim 1 and one or morepharmaceutically acceptable carriers and/or adjuvants.
 12. A method oftreating a disease or condition chosen from osteoarthritis,atherosclerosis, contact dermatitis, bone resorption diseases,reperfusion injury, asthma, multiple sclerosis, Guillain-Barre syndrome,Crohn's disease, ulcerative colitis, psoriasis, graft versus hostdisease, systemic lupus erythematosus, type I diabetes, rheumatoidarthritis, toxic shock syndrome, type II diabetes, inflammatory boweldiseases, acute and chronic pain, myocardial infarction alone orfollowing thrombolytic therapy, thermal injury, adult respiratorydistress syndrome (ARDS), multiple organ injury secondary to trauma,acute glomerulonephritis, dermatoses with acute inflammatory components,acute purulent meningitis, leukopherisis, necrotizing entrerocolitis,restenosis following percutaneous transluminal coronary angioplasty,traumatic arthritis, sepsis, chronic obstructive pulmonary disease andcongestive heart failure, said method comprising administering to apatient a pharmaceutically effective amount of a compound according toclaim
 1. 13. The compound according to claim 3 and wherein: J is chosenfrom C₁₋₁₀ alkyl, aryl and C₃₋₇ cycloalkyl each optionally substitutedby R^(b); R^(x) is independently chosen from C₁₋₆ alkyl which mayoptionally be partially or fully halogenated, acetyl, aroyl, C₁₋₄alkoxy, which may optionally be partially or fully halogenated, halogen,methoxycarbonyl, phenylsulfonyl and —SO₂—CF₃; R^(b) is chosen fromhydrogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, C₃₋₈ cycloalkylC₀₋₂alkyl, aryl, C₁₋₅ alkoxy, C₁₋₅ alkylthio, amino, C₁₋₅ alkylamino, C₁₋₅dialkylamino, C₁₋₅ acyl, C₁₋₅ alkoxycarbonyl, C₁₋₅ acyloxy, C₁₋₅acylamino, C₁₋₅ sulfonylamino, hydroxy, halogen, trifluoromethyl, nitro,nitrile, or R^(b) is chosen from heterocycle chosen from pyrrolidinyl,pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,1,3-dioxolanone, 1,3- dioxanone, 1,4-dioxanyl, piperidinonyl,tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene sulfoxide,pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxideand tetramethylene sulfone and heteroaryl chosen from aziridinyl,thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl,tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl,naphthyridinyl, indazolyl, triazolyl, pyrazolo[3,4 -b]pyrimidinyl,purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl,tubercidinyl, oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl; and R⁷hydrogen.
 14. The compound according to claim 13 and wherein: J ischosen from C₁₋₁₀ alkyl, phenyl, naphthyl and C₃₋₇ cycloalkyl eachoptionally substituted by R^(b); each R³, R⁴ and R⁵ are hydrogen.